Phenyl substituted-3-azabicyclo[3.1.0]hexanes, exemplified by bicifadine (p-toly-3-azabicyclo[3.1.0]hexane) and 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane have been reported to inhibit the uptake of biogenic amines (serotonin, norepinephrine and dopamine) that serve as neurotransmitters in the central nervous system. Basile, A. S., et al., J. Pharmacol. Exp. Ther., 321:1208-1225 (2007); Skolnick, P. et al., Eur. J. Pharmacol. 461:99 (2003); Skolnick, P. et al., Life Sci. 73: 3175-3179 (2003); Skolnick, P., et al., CNS Drug Reviews (2006)] Related compounds have also been described in U.S. patent application Ser. No. 11/371,178 filed on Mar. 7, 2006, which is related to and claims priority from US Provisional Applications 60/661,662, filed on Mar. 8, 2005 and 60/701,562 filed on Jul. 22, 2005, the disclosures of which are incorporated herein by reference in their entirety. Biogenic amines are widely distributed throughout the central nervous system and have been implicated in a variety of neurological and psychiatric disorders ranging from acute and chronic pain syndromes, and neuropathic disorders, to affective disorders such as depression and anxiety. [Briley, M., Hum. Psychopharmacol. Clin. Exp. 19:S21-S25 (2004); Skolnick, P. in “Dopamine and glutamate in psychiatric disorders,” W. Schmidt, Editor; Humana Press, Totowa, Chapter 9, pp. 199-214 (2005)]. Compounds inhibiting the uptake of these neurotransmitters (resulting in increased concentrations of norepinephrine, serotonin and/or dopamine in the synaptic cleft) may therefore be useful in treating these disorders. [Skolnick, P., et al., CNS Drug Reviews (2006); Briley, M., Hum. Psychopharmacol. Clin. Exp. 19:S21-S25 (2004)]
The effectiveness of a neurotransmitter uptake inhibitor in treating a neuropsychiatric disorder depends upon, at least in part, its relative potency as an inhibitor of serotonin versus norepinephrine versus dopamine uptake. For example, serotonin selective reuptake inhibitors (SSRIs) are commonly prescribed as antidepressants but are not very effective in treating pain [Atkinson, J. H. et al., Pain 83:137-145 (1999)], while compounds that inhibit the uptake of norepinephrine and serotonin (NSRIs) are useful in treating both depression and pain. Compounds inhibiting the reuptake of all three biogenic amines may have certain therapeutic advantages (e.g., faster onset; superior side effect profile) than single or dual uptake inhibitors. [Skolnick, P. et al., Eur. J. Pharmacol. 461:99 (2003); Skolnick, P. et al., Life Sci. 73: 3175-3179 (2003); Skolnick, P. in “Dopamine and glutamate in psychiatric disorders,” W. Schmidt, Editor; Humana Press, Totowa, Chapter 9, pp. 199-214 (2005)]
The ability of phenyl substituted azabicyclohexanes to inhibit biogenic amine uptake is effected through binding to a family of distinct but related transport proteins that have been identified and can readily be expressed as recombinant proteins. [Povlock, S. L. and Amara, S. G., in “Neurotransmitter transporters: structure, function, and regulation,” Reith M E A, Editor, Humana Press, Totowa, pp. 1-28 (1997); Eshleman, A. J. et al., Journal of Pharmacology & Experimental Therapeutics 289:877-885 (1999)] The potency of a compound to inhibit biogenic amine uptake can be measured by standard neurochemical techniques [Skolnick, P. et al., Eur. J. Pharmacol. 461:99 (2003)] including radioligand binding and [3H]biogenic amine (e.g., serotonin) uptake using such recombinant proteins expressed in, for example, a mammalian cell line. Such techniques are well known to those skilled in the art.
Notwithstanding the foregoing, there remains a compelling need to identify additional compounds that inhibit the reuptake of one, two, or three of these biogenic amines for the treatment of a variety of neurological and psychiatric disorders.